Project Summary Targeted immunotherapies such as monoclonal antibodies (mAbs) and CAR-T cells are highly successful against hematological malignancies. However, these diseases remain incurable due to emerging resistance such as to the anti-CD20 antibody, rituximab, or more recently CD19-CAR T cells. Thus, there is an urgent need to develop new therapies that target B-cell malignancies. We can circumvent resistance by generating a novel therapy against an alternative target. One target on B-cell tumors is B-cell activating factor receptor (BAFF- R/TNFRSF13C), a tumor necrosis factor receptor superfamily member involved in B lymphocyte development and survival. BAFF-R is expressed almost exclusively on B cells and its surface expression has been documented on various human B-cell lymphomas. The BAFF/BAFF-R axis was previously targeted for autoimmune diseases, however initial promise for tumor therapy has not yet been realized. We began to develop chimeric antibodies targeting BAFF-R as a practical solution to quickly address the unmet therapeutic need in drug-resistant B-cell lymphomas and leukemias. In our preliminary developments, our anti- BAFF-R antibody has demonstrated efficacy in several in vitro and in vivo models. Our chimeric antibodies demonstrated clear binding and potent antibody-dependent cell-mediated cytotoxicity (ADCC) against a range of B-cell NHL and primary lymphomas from patients who progressed following exposure to rituximab. In vivo, the anti-BAFF-R antibodies effectively eliminated tumors in drug-resistant lymphoma mouse models and conferred significantly greater survival to antibody treated mice compared with controls. The success thus far prompts our current hypothesis that BAFF-R is a suitable therapeutic antibody target for B- cell lymphomas and leukemias. Our Specific Aim 1 proposes to investigate the therapeutic potential of BAFF-R mAbs in relapsed B-cell malignancies resistant to CD19-target treatments. This aim will seek to develop and investigate models of CD19-therapy resistant diseases. BAFF-R antibodies will be tested against CD19-knock out tumor lines as well as primary patient samples from patients who relapsed with CD19-negative tumors. Specific Aim 2 proposes to humanize BAFF-R mAbs and validate the lead candidate. This aim focuses on the translatability and clinical relevance of our developed antibody. Humanizing the antibody will reduce negative human-anti-mouse immune response to murine protein motifs on the anti-BAFF-R antibody. Furthermore, validating the lead humanized antibody candidate in patient-derived xenograft (PDX) models will provide robust evidence in support of its clinical translation and potential efficacy. Our novel antibody is developed to target a B-cell tumor associated marker that has not been clinically targeted. Therefore, we seek to produce strong evidence to present before the FDA in an Investigational New Drug (IND) application for a first-in-human clinical trial of a novel therapeutic to treat drug-resistant B-cell malignancies.